by Alex Yule, PhD, Associate, Alacrita Consulting
Vaccine development has never lacked ingenuity, but progress has arguably been evolutionary rather than revolutionary. The concept of protection by injecting selected components of infectious agents rather than whole microorganisms would not greatly surprise Edward Jenner, and, other than the notable success of Bexero® (GSK), the first licensed serogroup B meningococcal vaccine, bioinformatics-based strategies have some way to go before Pasteur’s vaccine design principles of “isolate, inactivate and inject” can be consigned to history.
Twenty-first century vaccinology faces major challenges. Conventional vaccine manufacturing and deployment are taxed by the annual challenge of shifting influenza strains or in mounting large-scale response to “swine ‘flu”-like global pandemics; condensed development cycles are needed to deal with outbreaks of Zika and Ebola viruses, or whatever emerging pathogens tomorrow might bring; no effective vaccines exist for infections common in both developed and emerging economies, including HIV, Chlamydia, cytomegalovirus and tuberculosis.
Revolutions in vaccinology have proved elusive. The prospect of replacing expensive and complex vaccine manufacture with the injection of chemically-synthesised strands of DNA encoding one or more antigens has been pursued since the 1990s. Although simple in concept, and despite efforts to optimise plasmid design and delivery, low potency and unresolved safety issues have confined DNA vaccination to a few animal health products. Even after decades of attention, synthetic peptide vaccines designed to mimic a desirable selection of antigenic sequences still struggle to elicit robust immune responses and confer effective protection.
High profile buy-ins by vaccine industry majors suggest that a true technological revolution may, finally, be on the not too distant horizon. Protein synthesis requires DNA code to be rewritten in the form of another nucleic acid, messenger RNA (“mRNA”), prior to translation of the message by ribosomes, the cell’s protein factories. That the transcription of DNA can be circumvented through direct injection of mRNA to produce the corresponding protein has been known for decades, but the instability of mRNA, and the unwelcome complication that unmodified mRNA is itself highly immunogenic, led to the exploration of mRNA vaccination being sidelined by less technically demanding DNA and recombinant protein approaches.
Across the board advances in ease of delivery, improved stability through chemical modification and increased duration of protein production in vivo, are rapidly making mRNA vaccination a potentially viable proposition[1]. Clinical trials are underway in several infectious disease indications, including influenza, Zika virus and HIV infection, the latter exploring therapeutic rather than prophylactic potential. mRNA vaccine immunotherapy is under investigation in a variety of solid and haematological cancers, with the majority of studies exploiting specialised antigen-presenting cells (dendritic cells) which can be readily isolated from patients, loaded with mRNA encoding tumour antigen(s) and then returned by infusion.
Recent licensing agreements between mRNA vaccine developers and leading vaccine companies add to a growing list of industrial, governmental and not-for-profit collaborations aimed at leveraging the benefits that mRNA technology might bring to infectious disease vaccination: higher immunogenicity; inherent safety and rapid, low-cost, scalable manufacture.
Pfizer’s $425 million headline collaboration with mRNA vaccine developer BioNTech is focused on building better flu vaccines which can be manufactured quickly and cheaply[2]. In June, another mRNA vaccine pioneer, Translate Bio, entered in an $805 million headline agreement with Sanofi Pasteur which covers five undisclosed infectious disease agents, with the option to expand the collaboration to other pathogens[3]. CureVac AG has infectious disease mRNA vaccine partnerships with both Sanofi Pasteur and Johnson & Johnson, while GSK and Novartis are collaborating on mRNA vaccine development.
Early clinical data obtained with directly injected flu and rabies mRNA vaccines can best be described as “modestly encouraging” and it will be several years before which (if any) of the various flavours of mRNA technology can claim to offer a viable route to cost-effective, large scale vaccination, and/or a practical solution to problem pathogens. The picture may become clearer with the results from a second Phase I study of Moderna Therapeutics’s flu vaccine[4] and a Zika vaccine Phase I study[5], both due to complete before year end.
[1] mRNA vaccines — a new era in vaccinology. Pardi, N et al.Nature Reviews Drug Discovery (2018); 17:261-279. Published online 12th January, doi:10.1038/nrd.2017.243
[2] BioNTech signs collaboration agreement with Pfizer to develop mRNA-based vaccines for prevention of influenza. Company press release online 16th August 2018. http://tinyurl.com/y88mfkr7.
[3] Translate Bio announces closing of collaboration and licensing agreement with Sanofi Pasteur to develop mRNA vaccines for infectious diseases. Company press release online 9th July 2018. http://tinyurl.com/ycha48vp.
[4] Safety, Tolerability, and Immunogenicity of VAL-506440 in Healthy Adult Subjects NCT03076385
[5] Safety, Tolerability, and Immunogenicity of mRNA-1325 in Healthy Adult Subjects NCT03076385